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CORRESPONDENCE Recently, Holmberg et al reported on a strikingly high incidence
of cytomegalovirus (CMV) infection and disease in a cohort of patients
receiving high-dose chemotherapy followed by the infusion of autologous
CD34-selected peripheral blood progenitor cell transplants (PBPCTs). In
a multivariate logistic regression analysis, the use of CD34-selected
autologous peripheral blood stem cells after high-dose therapy was
associated with a marked increase in the incidence of CMV disease and
CMV-associated deaths.1 Here we report the incidence of CMV infection and disease following
allogeneic stem cell transplantation comparing recipients of
(a) unmanipulated allogeneic peripheral blood stem cells
from HLA-identical siblings (group I), (b) CD34-selected
allogeneic peripheral blood stem cells from HLA-identical (n = 15) or
1 Antigen-mismatch (n = 3) siblings (group II), and (c) a
group of patients receiving in vivo T-cell depleted bone marrow from
HLA-identical (n = 11) or 1 Antigen-mismatch (n = 4) unrelated
donors (group III). Patient characteristics for the 3 groups are shown
in Table 1. The Cellpro Ceprate System
(Cellpro, Seattle, WA) was used in all cases of group II to select
CD34+ cells. The median number of CD34+
cells/kg body weight (bw) was not different between groups I and II
(4.17 ± 0.53 × 106 versus
3.96 ± 1.05 × 106). CD34+ selection
resulted in a reduction of CD3+ cells from
188.1 ± 76.9 × 106 cells/kg bw (group I, n = 17) to
0.39 ± 0.24 × 106 cells/kg bw (group II, n = 18).
Graft-versus-host disease (GVHD)-prophylaxis consisted of cyclosporine
A (CSA) (all patients) plus methotrexate (group I, n = 6; group II,
n = 4) or antithymocyte globulin (ATG; Biomerieux, Paris, France) on
days All patients were monitored by a polymerase chain reaction (PCR)-assay once weekly and received preemptive antiviral therapy with ganciclovir at 2 × 5mg/kg bw or foscarnet at 2 × 60 mg/kg bw as reported previously.2 Overall, 12 of 19 patients receiving unmanipulated peripheral blood
stem cells developed CMV infection after transplantation, compared to
16 of 18 receiving CD34-selected stem cells and 15 of 15 after BMT from
an unrelated donor (group I versus group II, P = .12;
group I versus group III, P = .01) (Table 1). The time to
the first positive PCR result after transplantation was observed at a
median of 29.5 (3-44) days in group I, 24.5 (5-46) days in group II,
and 21 (8-33) days in group III (for group I versus group III,
P = 0.01, Wilcoxon rank test) (Figure
1). The time to clearance of viral DNA in
the blood after the initiation of antiviral therapy did not differ
between groups I and II (3.3 [0-10] weeks and 3.3 [0-10] weeks,
respectively), whereas it was significantly longer in patients after
BMT from an unrelated donor receiving an intensified GVHD-prophylaxis
regimen (median duration of DNAemia, 8.7 [range 2-18] weeks,
P = .0002, Wilcoxon rank test). CMV disease was documented
in 1 patient receiving unmanipulated allogeneic stem cells (fatal CMV
pneumonia), in 2 patients receiving CD34-selected stem cells (fatal CMV
pneumonia, n = 1; enteritis after day 100 after transplantation,
n = 1), and in 3 patients following BMT from an unrelated donor
accompanied by intensified GVHD prophylaxis (fatal IP, n = 1;
hepatitis, n = 1; late onset retinitis, n = 1).
The median numbers of CD3+ and CD8+ lymphocytes
per microliter of blood assessed at 3 and 6 months after
transplantation did not differ among the 3 groups. But reconstitution
of CD4+ T cells at 3 months was significantly delayed in
patients receiving bone marrow from unrelated donors compared to
patients receiving CD34+-selected allogeneic stem cells
(median 26, range 2-770 CD4+ T cells/µL versus a median
of 186, range 42-350 CD4+ T cells/µL,
P = .01, Wilcoxon rank test; see Table
2), and at 3 months in patients
developing CMV disease (median 4, range 2-65 CD4+ T
cells/µL, n = 3) compared to patients with asymptomatic CMV infection (median 70, range 5-770 CD4+ T cells/µL,
n = 25) or without signs of CMV reactivation (median 100, range
49-350 CD4+ T cells/µL, n = 5) (P = .08,
Wilcoxon rank test).
CMV infection was diagnosed by PCR in all patients prior to the onset of CMV-related clinical symptoms. But in 1 patient receiving CD34-selected stem cells, CMV-IP developed before a second positive PCR result was obtained 1 week later, indicating that the time from the first positive PCR result to the onset of clinical symptoms might be very short in patients receiving T-cell-depleted allografts. Thus patients receiving CD34-selected allogeneic stem cells from related donors may develop CMV infection quite soon after transplantation. But due to a rapid immune reconstitution and early initiation of antiviral therapy based on a PCR assay, no increase in CMV-related morbidity and mortality after CD34+-selected allogeneic stem cell transplantation was observed. Patients receiving bone marrow from unrelated donors followed by an intensified GVHD prophylaxis showed CMV PCR positivity even sooner after transplantation, but again PCR-based antiviral therapy was found to be safe with only 1 patient developing early fatal CMV disease as already reported previously.2 But this group seemed to be at an increased risk for late onset CMV disease most likely due to a delayed reconstitution of CMV-specific T-cell responses.3-5 In conclusion, as discussed by Holmberg et al and demonstrated in this study, the high incidence of CMV disease in recipients of CD34-selected stem cells can be reduced by the early initiation of preemptive antiviral therapy based on sensitive assays,1,6 but probably to the expense of an increased incidence of late-onset CMV disease, especially in patients with delayed immune reconstitution.7-9
Holger Hebart, Wolfram Brugger, Ulrich Grigoleit, Barbara Gscheidle, Juergen Loeffler, Hansjörg Schäfer, Lothar Kanz, and Hermann Einsele
Christian Sinzger Supported by the Sonderforschungsbereich 510, project B3, and the IZKF Tübingen, project IIC2. References
1.
Holmberg LA, Boeckh M, Hooper H, et al.
Increased incidence of cytomegalovirus disease after autologous CD34-selected peripheral blood stem cell transplantation.
Blood.
1999;94:4029-4035
2.
Einsele H, Ehninger G, Hebart H, et al.
Polymerase chain reaction monitoring reduces the incidence of cytomegalovirus disease and the duration and side effects of antiviral therapy after bone marrow transplantation.
Blood.
1995;86:2815-2820 3. Krause H, Hebart H, Jahn G, Müller CA, Einsele H. Screening for CMV-specific T cell proliferation to identify patients at risk of developing late onset CMV disease. Bone Marrow Transplant. 1997;19:1111-1116[CrossRef][Medline] [Order article via Infotrieve].
4.
Small TN, Papadopoulos EB, Boulad F, et al.
Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions.
Blood.
1999;93:467-480
5.
Li CR, Greenberg PD, Gilbert KJ, Goodrich JM, Riddell SR.
Recovery of HLA-restricted cytomegalovirus responses after allogeneic bone marrow transplantation: correlation with CMV disease and effect of ganciclovir prophylaxis.
Blood.
1994;83:1971-1979 6. Hebart H, Schroeder A, Loeffler J, et al. Cytomegalovirus monitoring by polymerase chain reaction of whole blood samples from patients undergoing autologous bone marrow or peripheral blood progenitor cell transplantation. J Infect Dis. 1997;175:1490-1493[Medline] [Order article via Infotrieve]. 7. Boeckh M, Riddell SR, Cunningham T, Myerson D, Flowers M, Bowden RA. Increased risk of late CMV infection and disease in allogeneic marrow transplant recipients after ganciclovir prophylaxis is due to a lack of CMVspecific T-cell responses. Blood. 1996;88(suppl 1):643a. 8. Einsele H, Hebart H, Kauffmann-Schneider C, et al. Risk factors for treatment failures in patients receiving PCR-based preemptive therapy for CMV infection. Bone Marrow Transplant. 2000;25:757-763[CrossRef][Medline] [Order article via Infotrieve]. 9. Nguyen Q, Champlin R, Giralt S, et al. Late cytomegalovirus pneumonia in adult allogeneic blood and marrow transplant recipients. Clin Infect Dis. 1999;28:618-623[Medline] [Order article via Infotrieve].   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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4 to 
, allogeneic peripheral
blood stem cell transplantation (group I); 
,
CD34+-selected allogeneic peripheral blood stem cell
transplantation (group II); and 
, bone marrow transplantation from
an unrelated donor (in vivo T-cell depletion) (group III).
